ENGINEERING TARGETED NANOCARRIERS FOR TISSUE-SPECIFIC DELIVERY OF GENOME-BASED THERAPEUTICS

Abstract

Background: Genome-based therapeutics, such as the cellular enzyme CRISPR/Cas and RNA-based therapeutics, present hope in the fight against genetic and chronic diseases. But good and tissue-specific delivery remains highly challenging because of the presence of biological barriers, clearance by immune effectors, off target accumulation and poor internalization. The targeted nanocarriers have the potentials to enhance therapeutic precision, stability, and delivery efficiency.

Objective: The objective of this study was to design specific nanocarriers to efficiently deliver genome based therapeutic agents to specific tissues while minimizing possible systemic toxicity.

Methods: Nanocarriers made from lipids and polymers compatible with biological systems were created, and targeted with tissue-specific ligands. Engineered nanocarriers were used to codeliver CRISPR/Cas9 and RNA therapeutics and tested for their delivery efficacy by an in vitro/in vivo delivery assay. The conditions of cellular uptake, biodistribution, genome editing efficiency and cytotoxicity were carefully controlled.

Findings: Nanocarriers engineered for specific tissue uptake showed an average of 76–82% efficacy, with a 40% increase in the intracellular absorption of nanocarriers. The efficiency of the genome representation was enhanced by almost 35%, and off-target accumulation and cytotoxicity were greatly diminished. Improved internalization and therapeutic delivery was a result of enhanced cell internalization and controlled therapeutic delivery, respectively.

Conclusion: The precision, safety and efficiency of genome-based therapeutics are greatly improved by the targeted nanocarrier engineering approach that has immense potential in the application of advanced gene therapy and personalized nanomedicine.